Severe Immune Checkpoint Inhibitor Hepatitis in KRAS G12C-Mutant NSCLC Potentially Triggered by Sotorasib: Case Report
02 Aug 2021-Vol. 2, Iss: 9, pp 100213
TL;DR: Sotorasib is a first-in-class small molecule that irreversibly inhibits KRAS G12C, locking it in an inactive state, inhibiting oncogenic signaling, and inducing a proinflammatory microenvironment as discussed by the authors.
Abstract: Sotorasib is a first-in-class small molecule that irreversibly inhibits KRAS G12C, locking it in an inactive state, inhibiting oncogenic signaling, and inducing a proinflammatory microenvironment. Here, we report the first case of life-threatening hepatitis in a patient with NSCLC shortly after commencing sotorasib, in which biopsy result was consistent with checkpoint inhibitor (CPI) immune-related adverse event, implicating sotorasib as being able to trigger CPI immune hepatitis. Given the large proportion of patients potentially treatable with sequential sotorasib after CPI, coupled with limited trial data, sotorasib-triggered CPI immune-related hepatitis should be considered in patients with sotorasib hepatotoxicity.
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TL;DR: This review will discuss the novel therapeutic strategies targeting KRAS G12C and promising approaches of combined therapy to overcome acquired resistance to KRASG12C inhibitors.
Abstract: Although KRAS-activating mutations represent the most common oncogenic driver in non-small cell lung cancer (NSCLC), various attempts to inhibit KRAS failed in the past decade. KRAS mutations are associated with a poor prognosis and a poor response to standard therapeutic regimen. The recent development of new therapeutic agents (i.e., adagrasib, sotorasib) that target specifically KRAS G12C in its GDP-bound state has evidenced an unprecedented success in the treatment of this subgroup of patients. Despite providing pre-clinical and clinical efficacy, several mechanisms of acquired resistance to KRAS G12C inhibitors have been reported. In this setting, combined therapeutic strategies including inhibition of either SHP2, SOS1 or downstream effectors of KRAS G12C seem particularly interesting to overcome acquired resistance. In this review, we will discuss the novel therapeutic strategies targeting KRAS G12C and promising approaches of combined therapy to overcome acquired resistance to KRAS G12C inhibitors.
26 citations
TL;DR: The best first-line strategy remains to be determined and, due to the heterogeneity of KRAS, is likely to be based on combination therapies, and understanding the possible mechanisms of resistance and which drugs could be useful to overcome it is key.
Abstract: Kirsten Rat Sarcoma viral oncogene homolog (KRAS) is the most frequently altered oncogene in Non-Small Cell Lung Cancer (NSCLC). KRAS mutant tumors constitute a heterogeneous group of diseases, different from other oncogene-derived tumors in terms of biology and response to treatment, which hinders the development of effective drugs against KRAS. Therefore, for decades, despite enormous efforts invested in the development of drugs aimed at inhibiting KRAS or its signaling pathways, KRAS was considered to be undruggable. Recently, the discovery of a new pocket under the effector binding switch II region of KRAS G12C has allowed the development of direct KRAS inhibitors such as sotorasib, the first FDA-approved drug targeting KRAS G12C, or adagrasib, initiating a new exciting era. However, treatment with targeted KRAS G12C inhibitors also leads to resistance, and understanding the possible mechanisms of resistance and which drugs could be useful to overcome it is key. Among others, KRAS G12C (ON) tricomplex inhibitors and different combination therapy strategies are being analyzed in clinical trials. Another area of interest is the potential role of co-mutations in treatment selection, particularly immunotherapy. The best first-line strategy remains to be determined and, due to the heterogeneity of KRAS, is likely to be based on combination therapies.
16 citations
TL;DR: In this paper , the authors discuss the discovery, biology, and function of KRAS in human malignancies and discuss the relationship between KRAS mutations and the tumour microenvironment, and therapeutic strategies to target KRAS.
Abstract: Abstract After decades of efforts, we have recently made progress into targeting KRAS mutations in several malignancies. Known as the ‘holy grail’ of targeted cancer therapies, KRAS is the most frequently mutated oncogene in human malignancies. Under normal conditions, KRAS shuttles between the GDP-bound ‘off’ state and the GTP-bound ‘on’ state. Mutant KRAS is constitutively activated and leads to persistent downstream signaling and oncogenesis. In 2013, improved understanding of KRAS biology and newer drug designing technologies led to the crucial discovery of a cysteine drug-binding pocket in GDP-bound mutant KRAS G12C protein. Covalent inhibitors that block mutant KRAS G12C were successfully developed and sotorasib was the first KRAS G12C inhibitor to be approved, with several more in the pipeline. Simultaneously, effects of KRAS mutations on tumour microenvironment were also discovered, partly owing to the universal use of immune checkpoint inhibitors. In this review, we discuss the discovery, biology, and function of KRAS in human malignancies. We also discuss the relationship between KRAS mutations and the tumour microenvironment, and therapeutic strategies to target KRAS. Finally, we review the current clinical evidence and ongoing clinical trials of novel agents targeting KRAS and shine light on resistance pathways known so far.
9 citations
TL;DR: Clinical aspects of KRAS mutations in NSCLC will be focused on the emerging efficacy data of Sotorasib and other KRAS inhibitors, including mechanisms of resistance, and the interaction betweenKRAS mutations and immune checkpoint inhibitors will be discussed.
Abstract: Simple Summary Mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS) gene are the most common alterations in non-small cell lung cancer (NSCLC); they are generally linked to smoking history and are typical of the lung adenocarcinoma (AC) subtype. The clinical relevance of KRAS mutations in NSCLC was generally low or null until a few years ago. What is now emerging is that KRAS-mutant lung AC patients are generally associated with poorer survival. However, the approval of Sotorasib, a KRAS inhibitor, improved the survival of a previously untargetable KRAS-mutant lung AC group. Furthermore, new approaches targeting KRAS are under development. Starting from the description of the biology of KRAS-mutant NSCLC, the present review focuses on the clinical aspects of KRAS mutations in NSCLC. Finally, the interaction between KRAS mutations and immune checkpoint inhibitors will also be discussed. Abstract In non-small cell lung cancer (NSCLC) the most common alterations are identified in the Kirsten rat sarcoma viral oncogene homolog (KRAS) gene, accounting for approximately 30% of cases in Caucasian patients. The majority of mutations are located in exon 2, with the c.34G > T (p.G12C) change being the most prevalent. The clinical relevance of KRAS mutations in NSCLC was not recognized until a few years ago. What is now emerging is a dual key role played by KRAS mutations in the management of NSCLC patients. First, recent data report that KRAS-mutant lung AC patients generally have poorer overall survival (OS). Second, a KRAS inhibitor specifically targeting the c.34G > T (p.G12C) variant, Sotorasib, has been approved by the U.S. Food and Drug Administration (FDA) and by the European Medicines Agency. Another KRAS inhibitor targeting c.34G > T (p.G12C), Adagrasib, is currently being reviewed by the FDA for accelerated approval. From the description of the biology of KRAS-mutant NSCLC, the present review will focus on the clinical aspects of KRAS mutations in NSCLC, in particular on the emerging efficacy data of Sotorasib and other KRAS inhibitors, including mechanisms of resistance. Finally, the interaction between KRAS mutations and immune checkpoint inhibitors will be discussed.
9 citations
TL;DR: In this article , the authors discuss the efficacy and toxicities of the novel KRAS G12C inhibitors as well as other indirect strategies for targeting oncogenic KRAS mutations.
Abstract: Lung cancer continues to be a major cause of cancer related death globally. Therapies targeting driver mutations have significantly extended the survival of patients whose lung cancer cells harbor these mutations. Patients with KRAS mutations, however, lacked specific targeted therapy until the recent FDA approval of sotorasib, a specific inhibitor of KRAS G12C mutant protein. We will discuss the efficacy and toxicities of the novel KRAS G12C inhibitors as well as other indirect strategies for targeting oncogenic KRAS mutations. We will review the limited literature on acquired resistance to these inhibitors and the novel combinatorial treatment strategies that are being tested currently in clinical trials.
3 citations
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TL;DR: PD-(L)1 blockade followed by osimertinib is associated with severe irAE and is most frequent among patients who recently received PD-(L]1 blockade, as no severe iraes occurred with administration of other EGFR-TKIs.
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TL;DR: In this article, the authors identify a subset of patients predisposed to immune checkpoint blockade-related hepatitis who are distinguished by chronic expansion of effector memory CD4+ T cells (TEM cells).
Abstract: Treatment of advanced melanoma with combined PD-1/CTLA-4 blockade commonly causes serious immune-mediated complications. Here, we identify a subset of patients predisposed to immune checkpoint blockade-related hepatitis who are distinguished by chronic expansion of effector memory CD4+ T cells (TEM cells). Pre-therapy CD4+ TEM cell expansion occurs primarily during autumn or winter in patients with metastatic disease and high cytomegalovirus (CMV)-specific serum antibody titres. These clinical features implicate metastasis-dependent, compartmentalised CMV reactivation as the cause of CD4+ TEM expansion. Pre-therapy CD4+ TEM expansion predicts hepatitis in CMV-seropositive patients, opening possibilities for avoidance or prevention. 3 of 4 patients with pre-treatment CD4+ TEM expansion who received αPD-1 monotherapy instead of αPD-1/αCTLA-4 therapy remained hepatitis-free. 4 of 4 patients with baseline CD4+ TEM expansion given prophylactic valganciclovir and αPD-1/αCTLA-4 therapy remained hepatitis-free. Our findings exemplify how pathogen exposure can shape clinical reactions after cancer therapy and how this insight leads to therapeutic innovations.
25 citations
Memorial Sloan Kettering Cancer Center1, University of Texas MD Anderson Cancer Center2, Sarah Cannon Research Institute3, Roswell Park Cancer Institute4, University of Adelaide5, Fox Chase Cancer Center6, University of Duisburg-Essen7, Emory University8, Institut Gustave Roussy9, Amgen10, Washington University in St. Louis11
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University of Texas MD Anderson Cancer Center1, New Generation University College2, Aix-Marseille University3, Indiana University4, Sarah Cannon Research Institute5, Washington University in St. Louis6, Roswell Park Cancer Institute7, Samsung Medical Center8, Duke University9, University of Pittsburgh10, Amgen11, Memorial Sloan Kettering Cancer Center12
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